Modified release analgesic suspensions

ABSTRACT

A pharmaceutical dosage form comprising non-steroidal-anti-inflammatory drugs, in particular propionic acid derivatives such as ibuprofen, along with a second active ingredient having a shorter therapeutically effective plasma concentration duration, such as phenylephrine, and methods of administering the same are provided. This method provides improved therapeutic effect, in particular pain relief along with decongestant relief, over extended time periods.

This application claims priority to provisional Appl. No. 60,860,260,filed Nov. 21, 2006, which is hereby incorporated in its entirety.

The present invention relates to a modified release pharmaceuticalformulation suitable for liquid dosage forms for the administration ofat least two active ingredients. More specifically, the dosage formreleases the active ingredients at rates that provide pharmaceuticallysuitable plasma concentrations of all of the active ingredientscontained therein over a similar period of time.

BACKGROUND OF THE INVENTION

Therapeutic agents for treating pain, inflammation, and fever includeanalgesics, anti-inflammatories, and antipyretics. Non-steroidalanti-inflammatory drugs (NSAID's) are one type of such therapeuticagents. They include propionic acid derivatives, acetic acidderivatives, fenamic acid derivatives, biphenylcarbodylic acidderivatives, oxicams, and cyclooxygenase-2 (COX-2) selective NSAID's.

Propionic acid derivatives include for example ibuprofen, naproxen, andketoprofen. Ibuprofen in particular is a widely used, well known NSAIDpossessing analgesic and antipyretic properties. It has beencommercially available as an over-the-counter drug in many forms forseveral years. Ibuprofen is chemically known as2-(4-isobutylphenyl)-propionic acid.

Immediate release NSAID's are typically administered about every 4 to 6hours. Typically, a daily dose of NSAIDs range from about 50 to about2000 milligrams, preferably from about 100 to 1600 and most preferablyfrom about 200 to about 1200 milligrams.

Many other active ingredients are administered more frequently due totheir relatively shorter duration. For example, the therapeuticallyeffective plasma concentration of the decongestant phenylephrine isabout 2.5 hours±0.7 hours, and thus it is typically administered every 2to 4 hours.

In order to administer a single product containing an NSAID and anotheractive ingredient having a pharmaceutically suitable plasmaconcentration that was shorter in duration, it would be necessary tocontrol the release of the latter. It is well-known to reduce the rateof release of a drug or other active ingredient from a dosage form intothe gastro-intestinal (“g.i.”) fluids of a patient, especially in orderto provide prolonged action of the drug in the body.

The rate at which an orally delivered drug reaches its site of action inthe body depends on a number of factors, including the rate and extentof drug absorption into the blood through the g.i. mucosa. However,before a drug can be absorbed into the blood, it must first be dissolvedin the g.i. fluids. For many drugs, absorption across the g.i. membranesis relatively rapid compared to their dissolution in the g.i. fluids,which thereby renders the dissolution of the drug as the rate limitingstep in drug absorption. Therefore, a formulator may effectively controlthe rate of drug absorption into the blood by modifying the drug's rateof dissolution.

Because the onset and duration of the therapeutic efficacy of drugs varywidely, as do their respective absorption, distribution, metabolism, andelimination, it is known to modify the release of different drugs indifferent ways, or to have a first drug immediately released from thedosage form, while a second drug is released in a “modified” manner,e.g., either delayed or controlled.

Well known mechanisms by which a dosage form can deliver a drug at amodified rate (e.g. sustained, prolonged, extended or retarded release)include diffusion, erosion, and osmosis. It is often practical to designdosage forms that use a combination of the above mechanisms to achieve aparticularly desirable modified release profile for a particular activeingredient.

Disadvantageously, many modified release applications employ soliddosage units having a final large size and weight. The administration ofsuch dosage units presents a problem especially to those patients withdifficulty swallowing, such as children and the elderly. Therefore, itis further desirable to provide such modified release medicines eitherin a chewable or orally disintegratable solid form or a liquid form. Formany patients, liquid oral dosage forms are more preferred because theycan be swallowed without the additional step of chewing.

Oral liquid forms have been commonly used for many years to delivermedication with an immediate release profile. See e.g., U.S. Pat. Nos.5,374,659; 4,788,220; 4,975,465; and 5,183,829. However, theincorporation of a modified release medication into a liquid dosage formpresents significant formulation challenges. In particular, coated orchemically bonded particles are typically employed to carry the modifiedrelease portion of the drug. For example, U.S. Pat. No. 5,980,882discloses the use of a drug-resin complex along with a chelating agentfor delaying the release rate of the drug. U.S. Pat. No. 4,847,077discloses the use of water-permeable diffusion barrier coatings ondrug-resin complex particles in order to provide a prolonged continuousrelease of the drug.

The properties of such particles, as well as those of the liquid vehiclefor suspending them, must be compatible so that the particles can bemaintained in a uniformly dispersed state. A particular challenge is theprevention of a premature release of drug from the suspended particlesinto the suspension medium during the storage life of the liquid dosageform prior to ingestion by a patient. Additionally, the maintenance ofthe desired dissolution profile as well as the desired dose uniformityof the liquid dosage form throughout its shelf-life are additionalchallenges to be addressed in formulating an oral, liquid modifiedrelease suspension product. Disadvantageously, these issues are oftenencountered when formulating a product containing, for example, animmediate release ibuprofen and a modified release second activeingredient, such as phenylephrine, due to the interaction between theibuprofen and the modified release coating agents known in the art.

United States Patent Application 20060057205 discloses liquid dosageforms comprising phenylephrine and at least a second drug such as ananalgesic, wherein the dosage form comprises particles of a complex ofboth drugs with an ion-exchange resin and wherein the particles arecoated with a modified release coating such as a polymethacrylate.However, we have found that uncoated propionic acid derivatives such asibuprofen can interact with semipermeable modified release coatings,such as those containing ethyl cellulose and polymethacrylate.Deleteriously, this interaction often compromises the release rate andthe intended modified release properties of the coated drug.

Therefore, it would be desirable to have a modified release dosage formcontaining ibuprofen particles and modified release particles of anotheractive ingredient, such as phenylephrine, which is not only palatable,but is also in a stable form that guarantees the required releaseprofile after administration. In particular, it would further bedesirable to have such an analgesic product that provided both animmediate release dose of the ibuprofen and a sustained release dose ofthe second active ingredient to the user without interaction between theibuprofen and the sustained release coating.

SUMMARY OF THE INVENTION

The invention provides a pharmaceutical dosage form, such as a dosageform suitable for the administration of NSAIDS in a liquid suspension,said dosage form comprising, consisting of, and/or consistingessentially of:

-   -   a) a first portion containing first active ingredient, such as        an NSAID, wherein the first active ingredient is released from        the dosage form in a substantially immediate manner upon contact        of the dosage form with a dissolution medium; and    -   b) a second portion containing        -   i) ion exchange resin particles having a second active            ingredient, which may be the same or different than the            first active ingredient and in one embodiment may be as            phenylephrine, bound thereon to form drug-resin complex            particles;        -   ii) a semi-permeable coating layer substantially covering            each of said drug-resin complex particles; and        -   iii) a protective coating layer substantially covering each            of said particles in ii),            wherein the second active ingredient is released from the            second portion in a modified release manner upon contact of            the dosage form with the dissolution medium, and wherein the            duration of the therapeutic effect of the second active            ingredient as released from the second portion of the dosage            form is substantially the same as the duration of the            therapeutic effect of the first active ingredient, and            methods for its administration as claimed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the percentage released (i.e. dissolution) ofphenylephrine in particles coated with an ethylcellulose semipermeablecoating layer as prepared in accordance with Example 4 versus time inthree different media.

FIG. 2 depicts the percentage released (i.e. dissolution) ofphenylephrine in particles coated with an ethylcellulose semipermeablecoating layer and an exterior enteric coating layer as prepared inaccordance with Example 5 versus time in three different media.

FIG. 3 depicts the percentage released (i.e. dissolution) ofphenylephrine in particles coated with an ethylcellulose coating layerin a suspension containing immediate release ibuprofen as prepared inaccordance with Example 7 versus time.

FIG. 4 depicts the percentage released (i.e. dissolution) ofphenylephrine in particles coated with an ethylcellulose coating layerand an exterior enteric coating layer in suspension containing immediaterelease ibuprofen as prepared in accordance with Example 8 versus time.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that one skilled in the art can, based upon thedescription herein, utilize the present invention to its fullest extent.The following specific embodiments are to be construed as merelyillustrative, and not limitative of the remainder of the disclosure inany way whatsoever.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the invention belongs. Also, all publications, patentapplications, patents, and other references mentioned herein areincorporated by reference. As used herein, all percentages are by weightunless otherwise specified. In addition, all ranges set forth herein aremeant to include any combinations of values between the two endpoints,inclusively.

As used herein, the term “substantially covers” or “substantiallycontinuous” means that the coating is generally continuous and generallycovers the entire surface of the core or underlying layer, so thatlittle to none of the active ingredient or underlying layer is exposed.

As used herein, “ATDAIRD” shall mean the average therapeutic duration ofaction of an effective immediate release dose” of a particular activeingredient. For example, the typical duration of action, i.e. period oftherapeutic effect, of an immediate release dose of ibuprofen orketoprofen is about 4 to about 6 hours. Accordingly, the ATDAIRD foribuprofen or ketoprofen is 5 hours. The typical duration of action of animmediate release dose of naproxen is about 8 to about 12 hours. TheATDAIRD for naproxen, therefore is 10 hours. The typical duration ofaction of an immediate release dose of phenylephrine is about 2 to about4 hours. The ATDAIRD for phenylephrine, therefore is 3 hours. Thetherapeutic duration of action of a particular active ingredient canreadily be determined from the dosing instructions in the labeling forimmediate release products containing that particular active ingredient.

As used herein, “modified release” shall apply to the altered release ordissolution of an active ingredient in a dissolution medium, such asg.i. fluids. The active ingredient or ingredients that may be releasedin a modified manner may be contained within, for example, dosage forms,coatings, or particles, or in any portion thereof, such as, for example,particles dispersed throughout a liquid suspending medium. Types ofmodified release include: 1) extended release; or 2) delayed release. Ingeneral, modified release dosage forms are formulated to make the activeingredient(s) available over an extended period of time after ingestion,which thereby allows for a reduction in dosing frequency compared to thedosing of the same active ingredient(s) in a conventional dosage form.Modified release dosage forms also permit the use of active ingredientcombinations wherein the duration of one active ingredient may differfrom the duration of another active ingredient.

By “extended release,” it is meant that, after administration, an activeingredient is released from the dosage form in a substantiallycontinuous, regulated manner, and the time for complete release, i.e.depletion, of the active ingredient from the dosage form is longer thanthat associated with an immediate release dosage form of the same. Typesof extended release include controlled, sustained, prolonged, zero-orderrelease, and the like.

By “delayed release,” it is meant that, after administration, there isat least one period of time when an active ingredient is not beingreleased from the dosage form, i.e. the release of the activeingredient(s) occurs at a time other than immediately following oraladministration.

As used herein, “dissolution medium” shall mean any suitable liquidenvironment in which the suspension dosage form of the present inventioncan be dissolved, such as, for example, the in vitro dissolution mediaused for testing of the product, or gastro-intestinal fluids. Suitablein vitro dissolution media used for testing the dissolution of theactive ingredient or ingredients from the suspension dosage form of thepresent invention include those described on page 786 of USP 23 (1995),which is incorporated by reference herein.

As used herein, “substantially coated” shall mean that less than about20%, e.g. less than about 15%, or less than about 1.0% of the surfacearea of a particle is exposed, e.g. not covered, with a desired coating.

“Enteric” shall mean being able to be dissolved at a pH of greater thanabout 5.0 or greater than about 5.5 or greater than about 6.0 or thatwhich is found in the intestines.

“Liquid dosage forms” may nonexclusively include suspensions or elixirs,wherein one or more of the active ingredients is dissolved, partiallydissolved or in an undissolved or suspended state.

As used herein “drug-resin complex” shall mean the bound form of any ofthe active ingredients, including but not limited to the pharmaceuticalactive ingredients, and the ion exchange resin. The drug-resin complexis also referred to in the art as a “resinate”.

As used herein, “immediate release” means that the dissolutioncharacteristics of at least one active ingredient meets USPspecifications for immediate release tablets containing that activeingredient. An active ingredient having an immediate release propertymay be dissolved in the gastro-intestinal contents, with no intention ofdelaying or prolonging the dissolution of the active ingredient. Forexample, for acetaminophen tablets, USP 24 specifies that in pH 5.8phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at least80% of the acetaminophen contained in the dosage form is releasedtherefrom within 30 minutes after dosing, and for ibuprofen tablets, USP24 specifies that in pH 7.2 phosphate buffer, using USP apparatus 2(paddles) at 50 rpm, at least 80% of the ibuprofen contained in thedosage form is released therefrom within 60 minutes after dosing. SeeUSP 24, 2000 Version, 19-20 and 856 (1999). Additionally, ibuprofensuspension may be analyzed for dissolution using pH 5.6 acetate bufferusing USP apparatus 2 (paddles) at 50 rpm, where at least 80% of theibuprofen contained in the dosage form is released therefrom within 60minutes after dosing for an immediate release dose.

As used herein, a drug “release rate” refers to the quantity of drugreleased from a dosage form per unit time, e.g., milligrams of drugreleased per hour (mg/hr). Drug release rates are calculated under invitro dosage form dissolution testing conditions known in the art. Asused herein, a drug release rate obtained at a specified time “followingadministration” refers to the in vitro drug release rate obtained at thespecified time following commencement of an appropriate dissolutiontest, e.g. those set forth in USP 24.

“Therapeutic effect,” as used herein, shall mean any effect or action ofan active ingredient intended to diagnose, treat, cure, mitigate, orprevent disease, or affect the structure or any function of the body.

“Semipermeable,” as used herein, shall mean that water can pass through,and other molecules, including salts and the active ingredientsdescribed herein, are allowed to slowly diffuse through such a membranewhen the membrane is in contact with an appropriate dissolution medium,e.g. gastro-intestinal fluids or in-vitro dissolution media.

As used herein, “water insoluble” shall mean compositions that aresubstantially insoluble, practically insoluble or only slightly solublein water as defined by U.S. Pharmacopeia, 24th edition. Thesecompositions require at least about 100 parts of solvent per part ofsaid composition, for complete dissolution.

“Erodible” as used herein shall mean the composition dissolves viasurface erosion when in contact with an appropriate dissolution medium.

As used herein, the “protective coating” shall mean a coating that doesnot react with the other particles or other active ingredients in thedry vehicle, e.g. the matrix, of the dosage form or, in liquid dosageform embodiments, the liquid vehicle medium.

As used herein, the term “phenylephrine” means benzynemethanol,3-hydroxy-α-[(methylamino)methyl], and includes, but is not limited topharmaceutically acceptable salts, esters, isomers or derivativesthereof.

As used herein, a “particle” is a crystal, a granule, an agglomerate, orany undissolved solid material.

One embodiment of the present invention is directed to a modifiedrelease pharmaceutical dosage form suitable for the administration ofactive ingredients containing: a) an immediate release portion, e.g., aportion containing at least one active ingredient that is immediatelyreleased from the dosage form; and b) a modified release portion, e.g. aportion containing at least one active ingredient that is released intothe bloodstream in a substantially continuous manner over a modifiedperiod of time.

In one embodiment, the active ingredient is released from the secondportion in a modified release manner upon contact of the dosage formwith the dissolution medium such that the modified release therapeuticeffect of the second active ingredient as released from the secondportion of the dosage form is substantially the same as the duration ofthe immediate release therapeutic effect of the first active ingredient.“Substantially the same as the duration of the immediate therapeuticeffect of the first active ingredient,” shall mean that the duration oftherapeutic effect of the second active ingredient is the same as orwithin about 1 hour, i.e., e.g., within about ½ hour or within about 15minutes or within about 10 minutes, of the duration of the first activeingredient. In another embodiment, the modified release therapeuticeffect of the second active ingredient as released from the secondportion of the dosage form may be, for example, at least from about 4hours to about 6 hours, or from about 4 hours to about 8 hours, or fromabout 4 hours to about 12 hours, after initial administration of thedosage form.

The immediate release portion may contain one or more active ingredientsthat are dispersed at the molecular level, e.g. melted or dissolved,within the dosage form, or the active ingredient may be in the form ofparticles, which in turn may be coated or uncoated. In embodimentswherein the active ingredient is in form of particles, the particles(whether coated or uncoated) typically have an average particle size offrom about 1 micron to about 2000 microns. In one embodiment, suchparticles are in the form of crystals having an average particle size ofabout 1 micron to about 300 microns. In another embodiment, theparticles are in the form of granules or pellets having an averageparticle size of about 25 microns to about 2000 microns, for example,from about 25 microns to about 1000 microns or from about 25 microns toabout 400 microns.

The modified release portion contains at least one active ingredient ina multiplicity of particles having modified release properties. In oneembodiment, the core of these particles in the modified release portionmay be comprised of the active ingredient in a pure, crystalline form,which is substantially coated with a modified release composition.Alternatively, the particle cores may be comprised of a mixture ofgranules comprised of one or more active ingredients with optionalingredients, such as binders, excipients and the like known in the art,and such granules are also substantially coated with a modified releasecomposition. In another embodiment, the active ingredient particles maybe dispersed throughout a matrix comprised of a modified releasecomposition.

In yet another embodiment, one or more active ingredients may bechemically bound or “complexed” to a resin, e.g. an ion exchange resin,to form drug-resin complex particles (or active ingredient resinparticles), which are first substantially coated with a semipermeablecoating layer, then substantially coated with a protective coatinglayer. One skilled in the art would readily appreciate without undueexperimentation that the particular ion exchange resin for use in thisembodiment is dependent upon several factors such as, for example, theionic charge of the active ingredient. An example of a suitable ionexchange resin for NSAID active ingredients includes, but is not limitedto, styrene/divinyl benzene copolymers and cholestyramines, which arecommercially available from Rohm & Haas under the tradename, “Duolite®AP143.” An example of a suitable ion exchange resin for positivelycharged active ingredients, such as phenylephrine or pseudoephedrine,includes, but is not limited to, an sulfonic acid cationic ion exchangeresin derived from a sulfonated styrene/divinyl benzene copolymer, suchas those commercially available from Rohm & Haas under the generaltradename “Amberlite,” e.g., “Amberlite IRP69,” and those commerciallyavailable from Dow Chemical Company, sold under the tradename, “Dowex,”e.g., “Dowex Marathon,” “Dowex Monosphere,” and “Dowex XYS-40010.00.”The Amberlite IRP 60 and Dowex XYS-40010.00 products are sulfonatedpolymers comprised of polystyrene cross-linked with about 8% ofdivinylbenzene, with an ion exchange capacity of about 4.5 to 5.5 meq./gof dry resin (H+-form). The Amberlite IRP-69 product is comprised ofirregularly-shaped particles with a particle size range of about 47 μmto about 149 μm, whereas the Dow XYS-40010.00 product is comprised ofspherical particles with a particle size range of about 45 μm to about150 μm. Another suitable ion exchange resin, “Dow XYS-40013.00,” is apolymer comprised of polystyrene cross-linked with about 8% ofdivinylbenzene and functionalized with a quaternary ammonium group; itsexchange capacity is normally within the range of about 3 to about 4meq./g of dry resin. Another suitable ion exchange resin includespolacrilin potassium, which is also known as methacrylic acid polymerswith divinylbenzene potassium salt. Suitable examples of polacrinpotassium include, but are not limited to those commercially availablefrom Rohm & Haas under the tradename, “Amberlite IRP-64,” which is acationic ion exchange resin that is derived from a copolymer ofmethcrylic acid and divinyl benzene. Additional details of complexationwith polymeric resins are well known in the art and disclosed in, forexample, U.S. Pat. Nos. 4,221,778; 5,980,882; 4,847,077; and 6,001,392.

Ion exchange resins are generally classified into various types,including strong acid cations, strong base cations, weak acid cationsand weak base cations. In general, the drug is mixed with an aqueoussuspension of a suitable resin, and the resin-drug complex is thenwashed and dried. Binding of the drug onto the resin may be demonstratedby analyzing the pH of the media eluting from the wash or by measuring achange in sodium concentration of the wash.

In embodiments wherein it is desirable to bind phenylephrine to an ionexchange resin via an aqueous mixture, the phenylephrine hydrochloride(PHE-HCl) and the resin may first be combined into a mixture. Then, thesodium ion of the resin may be exchanged with the protonated form ofphenylephrine (PHE-H⁺). Typically, the resulting drug-resin complex hasa weight ratio of phenylephrine to resin of about 20:80 to about 80:20,i.e., e.g. from about 30:70 to about 70:30.

In one particular embodiment, the modified release portion of the dosageform is substantially free of ion exchange resins. By “substantiallyfree of ion exchange resins,” it is meant that the amount of ionexchange resin, based upon the total weight of all active ingredientparticles in the dosage form, is less than about 1 percent, e.g., lessthan about 0.5 percent or less than about 0.1 percent.

In accordance with the present invention, the drug-resin complexparticles are substantially coated with a semipermeable coating. By“substantially coated,” it is meant that about 80%, e.g., about 85% orabout 99% of the particle surface is coated.

Examples of suitable semipermeable coatings include but are not limitedto, polymers such as cellulose acetate, ethylcellulose, non-entericpolymethacrylates and copolymers and mixtures thereof. Exemplarynon-enteric polymethacrylates include, but are not limited to,poly(ethyl acrylate, methyl methacrylate) 2:1, which is commerciallyavailable from Rohm Pharma under the tradename, “EUDRAGIT NE”;poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1 whichis commercially available from Rohm Pharma under the tradename “EUDRAGITFS;” poly(ethyl acrylate, methyl methacrylate, triethylammonioethylmethacrylate chloride) 1:2:0.2, which is commercially available fromRohm Pharma under the tradename “EUDRAGIT RL”; poly(ethyl acrylate,methyl methacrylate, triethyleammonioethyl methacrylate chloride1:2:0.1, which is commercially available from Rohm Pharma under thetradename “EUDRAGIT RS,” and copolymers and mixtures thereof. Celluloseacetate, which is also known in the art under the general terms ofacetyl cellulose, cellulose diacetate, and cellulose triacetate, iscommercially available from the Eastman Chemical Company.Ethylcellulose, which is also known in the art as cellulose ethyl ether,is commercially available from the Dow Corporation under the tradename“ETHOCEL.” In one embodiment, the semipermeable coating may be selectedfrom cellulose acetate, ethylcellulose, and mixtures thereof.

The coated drug-resin complex particles are then substantially coatedwith a protective coating. By “substantially coated,” it is meant thatabout 80%, e.g., about 85% or about 99% of the coated particle surfaceis then coated with a protective coating layer.

Examples of suitable protective coatings include those comprised ofenteric polymers including, but not limited to hydroxypropylmethylcellulose phthalate (also known as hypromellose phthalate),hydroxypropyl methylcellulose acetate succinate, cellulose acetatephthalate, polyvinylacetate phthalate, shellac, entericpolymethacrylate-based polymers, and copolymers and mixtures thereof.Examples of suitable enteric polymethacrylate-based polymers include,but are not limited to poly(methacrylic acid, methyl methacrylate) 1:2,which is commercially available from Rohm Pharma GmbH under thetradename, “EUDRAGIT S” polymers; poly(methacrylic acid, methylmethacrylate) 1:1, which is commercially available from Rohm Pharma GmbHunder the tradename, “EUDRAGIT L-100, L-30D, L 12.5 and L12.5 P”polymers; and poly(methacrylic acid, ethyl acrylate) 1:1 which iscommercially available from Rohm Pharma under the tradename “EUDRAGITL30-D 55 and L-100-55,” from Eastman Chemical under the tradename“Eastacryl 30D,” from Colorcon Corporation under the tradename,“Acryl-EZE” and from BASF Fine Chemicals under the tradename, “KollicoatMAE 30D.” In one embodiment, the enteric polymer may be selected fromnon-acrylate compounds, such as hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, cellulose acetatephthalate, polyvinylacetate phthalate, shellac and copolymers andmixtures thereof.

In one embodiment, the protective coating may also be provided in theform of a lipid, such as a fatty acid ester, a wax, or mixtures thereof.Examples of suitable fatty acid esters include, but are not limited tosucrose fatty acid esters; mono-di- and triglycerides; glycerylbehenate; glyceryl palmitostearate; glyceryl tristearate; glyceryltrilaurylate; glyceryl myristate; GLYCOWAX-932; lauroyl macrogol-32glycerides; stearoyl macrogol-32 glyceride; fatty acid esters such asthose having a fatty acid chain length of about C₁₀-C₄₀; and mixturesthereof.

Examples of suitable waxes include, but are not limited to carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, carnuba wax,beeswax, microcrystalline wax, and paraffin wax and the like, andmixtures thereof.

Optionally, the semi-permeable coating and/or the protective coating mayinclude a plasticizer. Examples of suitable plasticizers include, butare not limited to, polyethylene glycol; propylene glycol; glycerin;sorbitol; triethyl citrate; tributyl citrate; dibutyl sebecate;vegetable oils such as castor oil, rape oil, olive oil, and sesame oil;surfactants such as polysorbates, sodium lauryl sulfates, anddioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate ofglycerol; triacetate of glycerol; natural gums; triacetin;acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate;diethylmalonate; dioctylphthalate; dibutylsuccinate;glyceroltributyrate; glycerol monostearate; hydrogenated castor oil;substituted triglycerides and glycerides; and mixtures thereof.

In one embodiment, a suitable plasticizer may be used in an amount,based upon the total dry weight of the semi-permeable coating, fromabout 0.1% to about 40%, e.g. about 1% to about 30% or from about 5% toabout 20%.

In one embodiment, a suitable plasticizer may be used in an amount,based upon the total dry weight of the protective coating, from about0.1% to about 40%, i.e., e.g., from about 1% to about 30% or from about5% to about 20%.

In one embodiment, the weight ratio of the semipermeable coating layerto the protective, enteric coating layer in the modified releaseparticles is about 10:90 to about 90:10, or about 20:80 to about 80:20.

In one embodiment, the modified release particles are substantially freeof enteric polymers, i.e., e.g. the modified release particles contain,based upon the total weight of the modified release particles, less thanabout 1 percent or less than about 0.25 percent of enteric polymers.

In one embodiment, the drug-resin complex may be treated with asolvating or impregnating agent that is added while the activeingredient and the resin are being mixed or after the active ingredientis bound to the resin. Examples of suitable impregnating agents include,but are not limited to, sorbitol, polyethylene glycol, glycerol,propylene glycol, mannitol, lactitol, lactose, methylcellulose, andmixtures thereof. The impregnating agent may be present in an amount ofabout 5 parts to about 50 parts per weight of the dry resin.

In one embodiment, a chelating agent may be added to the dosage form inorder to stabilize the drug-resin complex by inhibiting the oxidation ofthe drug-resin complex. Suitable chelating agents include, but are notlimited to, ethylenediaminetetraacetic acid (EDTA) and salts of EDTAincluding, but not limited to, edetate calcium disodium, edetatetrisodium, edetate disodium, and edetate sodium. The chelating agent maybe present in an amount of about 0.005 percent to about 10 percent byweight of the final dosage form.

The active ingredient-resin complex particles, which contain a firstsemipermeable coating layer underneath a second protective coatinglater, yield a modified release composition that contains, based uponthe total dry weight of such modified release composition, from about 1percent to about 99 percent, e.g. from about 5 percent to about 80percent of the first semipermeable coating layer and from about 5percent to about 99 percent, e.g. from about 10 percent to about 90percent of the second protective coating layer.

The thickness of each of the two coating layers may vary depending uponthe modified release properties desired, the active ingredient selected,and the like, but typically may range from about 0.01 microns to about500 microns, e.g., from about 0.1 microns to about 100 microns.

The dry weight per surface area of the first coating layer on theparticles is about 0.1 mg/cm² to about 10 Mg/cm², i.e., e.g. from about0.5 mg/cm² to about 5 mg/cm². The dry weight per surface area of thesecond coating layer on the particles is about 0.1 mg/cm² to about 10mg/cm², e.g. about 0.5 mg/cm² to about 8 mg/cm².

The weight gain of the active ingredient-resin complex particles afterthe addition of the first semipermeable coating layer thereto is, basedupon the dry weight of the uncoated, active ingredient-resin complexparticles, from about 1 percent to about 200 percent, e.g., from about20 percent to about 150 percent. The weight gain of the activeingredient-resin complex particles after the addition of the secondprotective coating layer is, based upon the dry weight of the activeingredient-resin complex particles coated with the first semipermeablecoating layer, from about 25 percent to about 400 percent, e.g., fromabout 40 percent to about 400 percent.

The coated active ingredient particles may be formed by any suitablemethod known in the art. Suitable particle forming and coating methodsinclude high sheer granulation, fluid bed granulation, e.g. rotorgranulation, fluid bed coating, wurster coating, coaccervation, spraydrying, spray congealing, and the like and are described for example inPharmaceutical Dosage Forms: Tablets Volume 3, edited by Herbert A.Lieberman and Leon Lachman, Chapters 2, 3, and 4 (1982).

In one embodiment wherein the particles are formed by binding the activeagent to an ion exchange resin to form a drug-resin complex, theresulting complex particles are first coated with the semipermeablelayer using wurster fluid bed coating, then coated using wurster fluidbed coating with an enteric layer. The coating materials may be sprayedonto the particles via a solution or dispersion containing solventsincluding but not limited to water, ethanol, methanol, acetone, hexane,cyclohexane, methylene chloride, isopropanol, and mixtures thereof. Seee.g., U.S. Pat. No. 4,847,077.

In one embodiment the average diameter of the drug-resin complex is fromabout 20 microns to about 400 microns, or about 20 microns to about 300microns. In one embodiment, the average diameter of the drug-resincomplex particles coated with the first coating layer is from about 20to about 800 microns, e.g. from about 50 microns to about 400 microns,and the average diameter of the drug-resin complex particles coated withboth the first and second coating layers is from about 50 to about 1000microns, e.g. from about 100 microns to about 400 microns.

The dosage form of the present invention contains one or more activeagents or ingredients. Suitable active ingredients broadly include, forexample, pharmaceuticals, minerals, vitamins and other nutraceuticals,oral care agents, flavorants and mixtures thereof. Suitablepharmaceuticals include analgesics, anti-inflammatory agents,antiarthritics, anesthetics, antihistamines, antitussives, antibiotics,anti-infective agents, antivirals, anticoagulants, antidepressants,antidiabetic agents, antiemetics, antiflatulents, antifungals,antispasmodics, appetite suppressants, bronchodilators, cardiovascularagents, central nervous system agents, central nervous systemstimulants, decongestants, oral contraceptives, diuretics, expectorants,gastrointestinal agents, migraine preparations, motion sicknessproducts, mucolytics, muscle relaxants, osteoporosis preparations,polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tractagents and mixtures thereof.

Suitable flavorants include menthol, peppermint, mint flavors, fruitflavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueurflavors and combinations and the like.

Examples of suitable gastrointestinal agents include antacids such ascalcium carbonate, magnesium hydroxide, magnesium oxide, magnesiumcarbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminumsodium carbonate; stimulant laxatives, such as bisacodyl, cascarasagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleicacid, and dehydrocholic acid, and mixtures thereof; H2 receptorantagonists, such as famotadine, ranitidine, cimetadine, nizatidine;proton pump inhibitors such as omeprazole or lansoprazole;gastrointestinal cytoprotectives, such as sucraflate and misoprostol;gastrointestinal prokinetics, such as prucalopride, antibiotics for H.pylori, such as clarithromycin, amoxicillin, tetracycline, andmetronidazole; antidiarrheals, such as diphenoxylate and loperamide;glycopyrrolate; antiemetics, such as ondansetron, analgesics, such asmesalamine.

Examples of suitable polydimethylsiloxanes, which include, but are notlimited to dimethicone and simethicone, are those disclosed in U.S. Pat.Nos. 4,906,478, 5,275,822, and 6,103,260, the contents of each isexpressly incorporated herein by reference. As used herein, the term“simethicone” refers to the broader class of polydimethylsiloxanes,including but not limited to simethicone and dimethicone.

In one embodiment of the invention, at least one active ingredient maybe selected from bisacodyl, albuterol, famotadine, ranitidine,cimetidine, prucalopride, diphenoxylate, loperamide, lactase,mesalamine, bismuth, antacids, and pharmaceutically acceptable salts,esters, isomers, and mixtures thereof.

In another embodiment, at least one active ingredient is selected fromanalgesics, anti-inflammatories, and antipyretics, e.g. non-steroidalanti-inflammatory drugs (NSAIDs), including a) propionic acidderivatives, e.g. ibuprofen, naproxen, ketoprofen and the like; b)acetic acid derivatives, e.g. indomethacin, diclofenac, sulindac,tolmetin, and the like; c) fenamic acid derivatives, e.g. mefenamicacid, meclofenamic acid, flufenamic acid, and the like; d)biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal, andthe like; e) oxicams, e.g. piroxicam, sudoxicam, isoxicam, meloxicam,and the like; f) cyclooxygenase-2 (COX-2) selective NSAIDs; g) aspirinand h) pharmaceutically acceptable salts of the foregoing.

In one particular embodiment, at least one active ingredient is selectedfrom propionic acid derivative NSAID, which are pharmaceuticallyacceptable analgesics/non-steroidal anti-inflammatory drugs having afree —CH(CH₃)COOH or —CH₂CH₂COOH or a pharmaceutically acceptable saltgroup, such as —CH(CH₃)COO—Na⁺ or CH₂CH₂COO—Na⁺, which are typicallyattached directly or via a carbonyl functionality to a ring system,preferably an aromatic ring system.

Examples of useful propionic acid derivatives include ibuprofen,naproxen, benoxaprofen, naproxen sodium, fenbufen, flurbiprofen,fenoprofen, fenoprofen calcium, flurbiprofen, tiaprofenic, oxaprozin,fenbuprofen, ketoprofen, indoprofen, pirprofen, carpofen, oxaprofen,pranoprofen, microprofen, tioxaprofen, suprofen, alminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, and pharmaceuticallyacceptable salts, derivatives, and combinations thereof.

In one embodiment of the invention, the propionic acid derivative isselected from ibuprofen, ketoprofen, flubiprofen, and pharmaceuticallyacceptable salts and combinations thereof.

In another embodiment, the propionic acid derivative is ibuprofen,2-(4-isobutylphenyl) propionic acid, or a pharmaceutically acceptablesalt thereof, such as the arginine, lysine, or histidine salt ofibuprofen. Other pharmaceutically acceptable salts of ibuprofen aredescribed in U.S. Pat. Nos. 4,279,926, 4,873,231, 5,424,075 and5,510,385, the contents of which are incorporated by reference.

In another particular embodiment of the invention, at least one activeingredient may be selected from acetaminophen, acetyl salicylic acid,ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac,cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceuticallyacceptable salts, esters, isomers, and mixtures thereof.

In another particular embodiment of the invention, at least one activeingredient may be selected from pseudoephedrine, phenylephrine,phenylpropanolamine, chlorpheniramine, dextromethorphan,diphenhydramine, clofedianol, astemizole, terfenadine, fexofenadine,loratadine, desloratadine, cetirizine, mixtures thereof andpharmaceutically acceptable salts, esters, isomers, and mixturesthereof.

In a particular embodiment the active ingredient that is bound to aresin complex is selected from phenylephrine, pseudoephedrine,dextromethorphan, diphenhydramine, chlorpheniramine and mixturesthereof. In one embodiment the resin based particles are bound usinghydrochloride and hydrobromide salts of phenylephrine, pseudoephedrine,dextromethorphan, diphenhydramine, chlorpheniramine, and mixturesthereof.

In another particular embodiment, at least one active ingredient is anNSAID or a pharmaceutically acceptable salts thereof, and the otheractive ingredient bound to the drug resin complex is phenylephrineand/or psuedoephedrine.

In one embodiment, a therapeutically effective amount of the activeingredient or ingredients may be present in a “unit dose volume,” whichcan be in the form of a powder or an aqueous suspension.“Therapeutically effective amount,” as used herein, is an amount ofactive ingredient that produces the desired therapeutic response uponoral administration. One skilled in the art can readily determine the“therapeutically effective amount” of an active ingredient for a givenpatient by considering factors such as, for example, the particularactive ingredient being administered; the bioavailabilitycharacteristics of the active ingredient; the dose regimen desired; theage and weight of the patient; and the like. As used herein, a “unitdose volume” may be any convenient volume for orally administering adose of a given product to a patient.

In this embodiment, the “unit dose volume” is typically accompanied bydosing directions, which instruct the patient to take an amount of theactive ingredient that may be a multiple of the unit dose volumedepending on, e.g., the age or weight of the patient. Typically the unitdose volume of the suspension will contain an amount of activeingredient that is therapeutically effective for the smallest patient.For example, suitable unit dose volumes may include one teaspoonful(about 5 mL), one tablespoonful (about 15 mL), one dropper, or onemilliliter.

According to the invention, a dosage form containing NSAID may beprovided to a mammal in need of treatment, in particular pain relieftreatment, in a single administration that provides for the release ofthe active ingredient in the blood over an extended time period, e.g.over about an 4 hour or about a 6 hour period. At time zero, an initialdose of the NSAID is provided, i.e. administered, to the mammal via ofthe active ingredient(s) in the immediate release dose portion. Thesecond active ingredient is then released into the blood throughoutabout the next four to about 6 hours from initial administration of theformulation containing the active ingredient via the activeingredient(s) in the modified release dose portion. In other words, theformulation still retains undissolved, second active ingredient afterabout four or about six hours from initial administration.

In practicing the present invention, the dosage form may be comprisedof, based upon the total weight of the active ingredient, from about0.01 percent to about 40 percent of an immediate release dose particleportion of the first active ingredient; and from about 0.01 percent toabout 40 percent, i.e., from about 0.01 percent to about 10 percent of amodified release dose portion of the dual coated second activeingredient. As used herein, “portion” shall mean the amount of theidentified active ingredient along with any optional components, butshall not include the liquid vehicle or, in solid dosage forms, thematrix or other dry vehicle into which the immediate release doseparticles may be combined. The immediate release dose portion and themodified release dose portion may be combined with an appropriatevehicle to form either: 1) a dry mixture that can be suspendedextemporaneously when needed; 2) a ready-to-use liquid dosage form, suchas an elixir or suspension; or 3) a solid or semi solid dosage form.

Suitable constituents of the vehicle can include, without limitation,solvents; structuring agents; swelling agents; surfactants; sugars;buffering substances such as citric acid and sodium citrate; glycine andhydrochloric acid, sodium phosphate, and potassium phosphate;preservatives and bacteriostatic agents such as esters ofp-hydroxybenzoic acid; colorants; and various flavorings and sweetenerscommonly used in pharmaceuticals.

Examples of suitable sweeteners include, but are not limited to anyknown sweetening agent such as sugars, sugar alcohols, high intensitysweeteners, and mixtures thereof. Suitable sugars include, but are notlimited to sucrose, dextrose, high fructose corn syrup, and maltose.Suitable sugar alcohols include, but are not limited to sorbitol,xylitol, and mannitol. Suitable high intensity sweeteners include, butare not limited to sucralose, aspartame, saccharin, and acesulfame K.

In one embodiment, an effective amount of a buffering agent is used inorder to have the pKa of at least one active ingredient contained in themodified release portion of the liquid suspension dosage form be greaterthan the pH of the overall liquid suspension dosage form.

In addition, the vehicle may also be comprised of water, or mixtures ofwater and a pharmaceutically acceptable water-miscible co-solvent knownin the art such as, for example, glycols, alcohols and glycerol.

In certain embodiments the dosage form may include any suspendingsystems known in the art, such as those that typically include one ormore structuring agents and/or one or more swelling agents. In oneembodiment, the dosage form contains, based upon the total weight of theliquid suspension dosage form, from about 0.1 percent to about 10percent, of a suspending system. Suitable suspending systems includethose disclosed in, for example, U.S. Pat. Nos. 5,374,659, 5,621,005,and 5,409,907, which are all incorporated by reference herein in theirentireties.

Structuring agents that are suitable for use in the present inventioninclude hydrophilic polymers such as hydrocolloids. Examples of suitablehydrocolloids include alginates, agar, guar gum, locust bean,carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan,maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gumarabic, inulin, karaya, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and combinations thereof. In certain embodimentsof the present invention, xanthan gum is the structuring agent.

Xanthan gum is a high molecular weight natural carbohydrate,specifically, a polysaccharide. One xanthan gum that is suitable for usein the present invention is a high molecular weight polysaccharideproduced by Xanthomonas campestris. Techniques and strains for producingthis polysaccharide are described in U.S. Pat. Nos. 4,752,580 and3,485,719, the disclosures of which are hereby incorporated byreference. In one embodiment, the xanthan gum may have a viscosity in aone percent salt solution of from about 1000 to about 1700 cP (mPa-sec),as measured at 25° C. with an LV model Brookfield Synchro-Lectricviscometer at 60 rpm, no. 3 spindle. Suitable xanthan gums are availablefrom, for example, CP Kelco, under the tradename, “Keltrol,” “KeltrolTF,” and “Keltrol 1000.”

A swelling agent, when exposed to an appropriate aqueous environment,expands without forming a network system. Pregelatinized starch is aparticularly good swelling agent. Pregelatinized starch, also known as“instantized” starch, is precooked so that it swells and begins tothicken instantly when added to cold water. One particularly suitablepregelatinized starch is prepared from modified, stabilized and waxy,maize food starch, and is commercially available from National StarchCompany as “INSTANT STARCH, ULTRASPERSE-M.” Other suitable swellingagents include, but are not limited to microcrystalline cellulose and/orhydroxypropylmethylcellulose.

In one embodiment, the suspending system is comprised of a xanthan gumstructuring agent with a pregelatinized starch swelling agent. Inanother embodiment, the suspending system is comprised of, based uponthe total weight of the liquid suspension dosage form, from about 0.01percent to about 1 percent or from about 0.05 percent to about 0.40percent of xanthan gum and from about 1 percent to about 10 percent orfrom about 0.5 percent to about 3.0 percent of a pregelatinized starchsuch as that commercially available from National Starch Company underthe tradename, “INSTANT STARCH, ULTRASPERSE-M.”

In embodiments wherein the dosage form is in a liquid form, e.g.,suspension or elixir, the pH of the liquid dosage form should beoptimized to minimize the solubility and maximize the chemical stabilityof any uncoated active ingredient contained therein. In one embodimentwherein the uncoated active agent is basic, e.g., calcium carbonate, thepH of the dosage form may be as close as possible to 2 pH units abovethe pKa of that basic uncoated active agent. In embodiments wherein theuncoated active agent is acidic, e.g., ibuprofen, the pH of the dosageform may be as close as possible to 2 pH units below the pKa of thatacidic uncoated active agent. In certain embodiments employing ibuprofenas the uncoated active agent, the pH of the dosage form may be in therange from about 1.0 to about 5.0, e.g., from about 1.0 to about 4.0.

The dosage form can be buffered using known pH adjusting agents tomaintain the pH of the suspension in the desired pH range. SuitablepH-adjusting agents may be present in the dosage form in amountssufficient to provide the desired degree of pH buffering. ThepH-adjusting agents will typically be present in the range of from about0 to about 1 gram per 100 mL of the dosage form.

In an embodiment containing ibuprofen as the uncoated active agent and asuspending system having alkaline polymers, such as for example sodiumcarboxymethylcellulose, the pH adjusting agent may be selected from weakorganic acids, such as citric acid, malic acid, glutamic acid, and thelike having acceptable taste characteristics for use in taste maskedoral suspensions.

In one embodiment, the dosage form may optionally contain antimicrobialpreservatives having an activity within the desired pH range of thedosage form. Preservatives useful in such pharmaceutical suspensionsinclude, but are not limited to, sodium benzoate, potassium sorbate,salts of edetate (also known as salts of ethylene diaminetetraaceticacid, or EDTA, such as, disodium edetate) and parabens (such as, methyl,ethyl, propyl and butyl p-hydroxybenzoic acids esters). Thepreservatives listed above are exemplary, but each preservative must beevaluated on an empirical basis, in each formulation, to assure thecompatibility and efficacy of the preservative. Methods for evaluatingthe efficacy of preservatives in pharmaceutical formulations are knownto those skilled in the art.

In certain optional embodiments, the dosage form of the invention mayemploy a surfactant for use as a wetting agent to aid in the dispersionof certain hydrophobic active agents. In certain other embodiments, thedosage form of the invention may be substantially free of surfactant. Asused herein, “substantially free of surfactant” shall mean that thesuspension contains less than about 0.1%, e.g., less than about 0.05% ofa surfactant. Examples of suitable surfactants include, but are notlimited to sorbitan oleate esters, such as polyoxyethylene sorbitanmonooleate also known as polysorbate 80.

In one embodiment, the dosage form is in the form of an aqueouspharmaceutical suspension composition and is comprised of, based uponthe total weight of active ingredient per volume (w/v or g/100 ml) ofthe aqueous pharmaceutical suspension, from greater than about 0 percentto about 30 percent, e.g. about 0.05 percent to about 20 percent, orabout 0.5 percent to about 10 percent, or about 0.5 percent to about 5percent, of the first active ingredient and from greater than about 0percent to about 10 percent, e.g. about 0.01 percent to about 10percent, or about 0.03 percent to about 5 percent, of the second,modified release active ingredient.

In another embodiment wherein the first active ingredient is ibuprofen,the amount of first active ingredient in the immediate release portionof the suspension dosage form is, based upon the total weight of firstactive ingredient per volume (w/v) of the aqueous suspension dosageform, from about 25 to about 400 mg, e.g. from about 50 mg to about 200mg per teaspoonful of aqueous suspension dosage form, or is about 20 mgof first active ingredient per 1 mL of the aqueous suspension dosageform, which is equivalent to, based upon the total weight of firstactive ingredient per volume (w/v) of the aqueous suspension dosageform, from about 0.25 percent to about 4 percent, and the second activeingredient is phenylephrine or pseudoephedrine, the amount of secondactive ingredient in the modified release portion of the suspensiondosage form is, based upon the total weight of second active ingredientper volume (w/v) of the aqueous suspension dosage form, from about 1 mgto about 20 mg, e.g. from about 1 mg to about 10 mg per teaspoonful ofaqueous suspension dosage form, or is about 1.5 mg of second activeingredient per 1 mL of the aqueous suspension dosage form, which isequivalent to, based upon the total weight of second active ingredientper volume (w/v) of the aqueous suspension dosage form, from about 0.01percent to about 0.3 percent.

One embodiment of the present invention is directed to a liquidmeasurable suspension composition that includes, based upon the totalweight of the suspension: a) from about 0.05 percent to about 40 percentof a first, immediate release active ingredient; b) from about 20percent to about 80 percent of water; c) from about 0.1 percent to about10 percent of a suspending system; d) from about 0 percent to about 40percent, e.g. from about 20 percent to about 40 percent of a sweeteningagent; e) from about 0 percent to about 0.5 percent of excipients; andfrom about 0.01 percent to about_(—)10 percent of a second portion ofmodified release particles.

In another embodiment, the dosage form of the present inventioncomprises, based upon the total weight of the dosage form, from about0.1 percent to about 10 percent, e.g. from about 0.1 to about 5 percentof the first, immediate release portion; and from about 0.05 percent toabout 10 percent, e.g. from about 0.05 percent to about 5 percent, ofthe second, modified release portion. In one embodiment, the second,modified release portion of the dosage form is comprised of, based uponthe total dry weight of the second portion, from about 5 percent toabout 80 percent, e.g. from about 5 percent to about 70 percent, of thefirst, semi-permeable coating layer; from about 10 percent to about 90percent, e.g., from about 10 percent to about 80 percent of the secondprotective coating layer; and from about 1 percent to about 50 percent,e.g., from about 1 percent to about 30 percent of the drug-resin complexparticles.

According to the present invention, the dosage form contains, based uponthe total weight of the dosage form, from about 0.1 percent to about 5percent, e.g., from about 0.5 percent to about 3 percent, of the firstactive ingredient; and from about 0.005 percent to about 1 percent,e.g., from about 0.01 percent to about 0.5 percent of the second activeingredient.

In certain embodiments, the viscosity of the suspension of the presentinvention may range from about 400 cps to about 1500 cps as measured bya Brookfield DV-I+ Viscometer using a # 31 spindle and speed of 12 rpmunder temperature conditions of about 25° C.

The dosage forms of the present invention are intended to deliver aneffective amount of a first active ingredient, such as an NSAID, whichhas an ATDAIRD of about 5, in the same dosage form as an effectiveamount of a second active ingredient, such as phenylephrine orpsuedoephedrine, which as has an ATDAIRD of about 3 in oneadministration such that both active ingredients can be released fromthe dosage form throughout the longer ATDAIRD period.

An “effective amount” of an analgesic is one that provides relief frompain in a patient. For example, a typical adult dose of ibuprofen mayrange from about 2.9 to about 12 mg/kg weight of the patient given every4 to 6 hours, for a typical daily dose ranging from about 11.6 to about72 mg/kg/day. Therefore, administration of an effective amount ofibuprofen to a typical 70 kg adult may involve once or twice dailyadministration of about 5 ml to about 60 ml of the formulation of thepresent invention containing, for example, 40 mg/ml ibuprofen. A typicalpediatric dose of ibuprofen may range from about 5 to about 10 mg/kggiven every 4 to 6 hours, for a typical daily dose ranging from about 20to about 60 mg/kg/day. Administration of an effective amount ofibuprofen to a typical 15 kg child may involve once or twice dailyadministration of about 5 ml to about 60 ml of the formulation of thepresent invention containing, for example, 20 mg/ml ibuprofen.

An “effective amount” of a decongestant is one that provides effectiverelief of congestion, i.e. a medication that breaks up congestion, asthat of the nasal passages and/or sinuses, by reducing swelling. Forexample, a typical adult dose of phenylephrine may range from about 0.14to about 0.29 mg/kg weight of the patient given every 6 hours, or about10 mg to about 20 mg given every 6 hours for a typical adult, with atypical daily dose ranging from about 0.60 to about 1.0 mg/kg/day, orabout 0.86 mg/kg/day or about 60 mg phenylephrine per day for thetypical adult. Therefore, administration of an effective amount ofphenylephrine to a typical 70 kg adult may involve once to four timesdaily administration of about 2.5 ml to about 10 ml, or about 5 mL, of aformulation of the present invention containing, for example, 3 mg/mlphenylephrine. A typical pediatric dose of phenylephrine may range fromabout 0.25 to about 0.75 mg/kg given every 2 to 4 hours, or about 3.75mg to about 11.25 mg given every 6 hours for a typical child, for atypical daily dose ranging from about 1.0 to about 2.7 mg/kg/day, orabout 2 mg/kg/day, or about 30 mg of phenylephrine per day for thetypical child. Administration of an effective amount of phenylephrine toa typical 15 kg child may involve once to four times dailyadministration of about 2.5 ml to about 10 ml of the formulation of thepresent invention containing, for example, 1.5 mg/ml phenylephrine.

In one embodiment, the oral administration of the dosage forms of thepresent invention provides the user with the first active ingredient,such as NSAIDs, in a modified release dose that continues to release thesecond active ingredient from the dosage form so that the duration ofits therapeutic effect is comparable to that of the first activeingredient.

In one embodiment, the liquid dosage form contains an immediate releaseportion containing both ibuprofen and phenylephrine, and a modifiedrelease portion containing an additional amount of phenylephrine. Inthis embodiment, the immediate release dose of ibuprofen may range fromabout 25 mg/5 mL to about 200 mg/5 mL of suspension, e.g. about 50 mg/5mL to about 200 mg/5 mL of suspension, and the immediate release dose ofphenylephrine may range from about 2.5 mg to about 15 mg immediaterelease phenylephrine/5 mL suspension; e.g. about 2.5 mg to about 10 mgimmediate release phenylephrine/5 mL suspension. In this embodiment, themodified release dose of phenylephrine may range from about 2.5 mg toabout 20 mg modified release phenylephrine/5 ml of suspension; e.g.about 5 to about 15 mg modified release phenylephrine/5 mL suspension.

Another embodiment of the present invention is directed to method foralleviating nasal and respiratory congestion in persons in need thereofwith the oral administration of pseudoephedrine or phenylepherine, aswell as ameliorating associated conditions such as headache, joint pain,watery nasal passages, weeping eyes, sinus congestion and pain,coughing, excessive exudating of mucus, and bronchitis by way ofadministering the subject dosage forms of the present invention to suchpersons.

Beneficially, we have unexpectedly found how to effectively stabilizethe release characteristics of the modified release portion of thedosage form throughout the shelf life of the product and throughout theperiod of treatment, regardless of whether the dosage form is designedas a liquid dosage form, such as a suspension, or as a dry dosage formthat can be reconstituted with water prior to administration.Specifically, we have overcome the challenge of preventing activeingredient release from the particles in the product prior to ingestion,while enabling modified release of active ingredient from those sameparticles in the g.i. fluids.

We further have found how to extend the duration of the therapeuticeffect of the second, coated active agent to a duration comparable tothat possessed by the uncoated, first active agent by overcoming theinteraction between the first active agent and the semi-permeablecoating on the second agent.

Advantageously, the formulations of the present invention may be used ina variety of formats including, for example, (i) accurately-measurablesingle dose dry formulations or liquid suspensions; (ii) multi-dosegranular formulations having significant dose flexibility obtainable bymeasuring different amount of granules to be resuspended on an as-neededbasis; (iii) multi-dose liquid suspensions; and (iv) concentrated dropsin which the active ingredient is suspended, which is particularlyuseful in pediatric applications.

In addition, since the formulation is convenient to administer andswallow, and the number of daily doses of active ingredient is reduced,the overall patient compliance is achieved. Additional benefits areanticipated in pediatric practice due to the ease of swallowing andadministering.

The following examples further illustrate the invention, but are notmeant to limit the invention in any way.

EXAMPLE 1 Preparation of Phenylephrine—Resin Complex Particles

2125.0 g of phenylephrine hydrochloride was dissolved in 2000.0 g ofdeionized water in a suitable stainless steel container. 2500.0 g ofAmberlite IRP-69 ion exchange resin, commercially available from Rohm &Haas Corporation, was added thereto and stirred using a laboratory mixerat 100 RPM for at least 12 hours. The resulting slurry was filteredthrough a Wattman #4 filter paper using vacuum filtration. The resultingsolid was air dried for 1-2 hours to yield wet resin particles, whichwere then dried in a Glatt fluid bed GPCG-1 drier for 10 minutes at 50°C. The resulting dry particles contained approximately 32.0%phenylephrine. The remaining, unbound phenylephrine remained in thefiltered slurry solution.

EXAMPLE 2 Preparation of Ethylcellulose Semipermeable First CoatingSolution

A coating solution was prepared by dispersing 690 grams ofethylcellulose, which is commercially available from Dow ChemicalCorporation under the tradename, “Ethocel 10 CPS,” 150 g ofacetyltributyl citrate (ATBC), and 20 mg of magnesium stearate USP in asolvent containing, based upon the total weight of the solvent, 3780 gof acetone and 3780 g of isopropyl alcohol (a 50:50 mixture) underambient conditions. The solution was mixed using a laboratory mixer at75 RPM for at least 60 minutes.

The resulting coating solution contained, based upon the total wetcoating solution, 8.19% of ethylcellulose, 1.78% acetyltributyl citrate,0.24% magnesium stearate, 44.89% acetone, and 44.89% isopropyl alcohol.The solution contained 10% solids. The relative amounts of solids were,based upon the total weight percent of the dried coating solution,80.23% ethylcellulose, 17.44% ATBC, and 2.33% magnesium stearate.

EXAMPLE 3 Preparation of Protective (Enteric), Second Coating Solution

A coating solution was prepared by dispersing 4193.1 g of methacrylatecopolymer dispersion (30% solids), commercially available under thetradename, “Eudragit L30D-55,” which is commercially available from RohmPharma, in 2396.0 g purified water, and mixed at 25 RPM under ambientconditions for 5 minutes. 50.8 g of glycerol monostearate and 126.8 g oftriethylcitrate were added thereto with mixing at 50 RPM for at least 30minutes.

The resulting coating solution contained, based upon the total wetcoating solution, 61.97% of Eudragit L30D-55 (30% of which are assolids), 0.75% glycerol monostearate, 1.87% triethylcitrate and 35.41%purified water.

The relative amounts of solids were, based upon the total weight percentof the dried coating solution, 87.63% Eudragit L30D-55, 3.53% glycerolmonostearate, and 8.83% of triethylcitrate.

EXAMPLE 4 Preparation of Drug-Resin Phenylephrine Complex Coated with aSingle, Semipermeable Ethylcellulose Layer

1000.0 grams of the drug-resin complex particles from Example 1 wereplaced into a Glatt GPCG-1/3 coating unit and coated with theethylcellulose coating solution prepared in accordance with Example 2 byspraying the solution at a rate of about 15.0 g/min under producttemperature conditions of about 37-42° C., with an atomization airpressure of approximately 2 bar. The resulting coated phenylephrinegranules contained, based upon the total dry weight of the coatedphenylephrine granules, about 47.9% of the semipermeable coating.

EXAMPLE 5 Preparation of Drug-Resin Phenylephrine Complex Coated with anSemipermeable Layer and an Outer Enteric Layer

750.0 grams of the coated phenylephrine particles prepared in accordancewith Example 4 were placed into a Glatt GPCG-1/3 coating unit and coatedwith the enteric Eudragit L30D coating solution prepared in accordancewith Example 3 by spraying the solution at a rate of about 15.0 g/minunder product temperature conditions of about 54-71° C., and with anatomization air pressure of approximately 2 bar. The resulting coatedphenylephrine granules contained, based upon the total dry weight of thedouble-coated phenylephrine granules, about 65.7% of the outer,protective enteric coating. The amount of ingredients in the finaldried, double-coated particles are shown in Table 1.

TABLE 1 Dried Coated Particle Formulation Percent Ingredients Tradename% (w/w) Phenylephrine HCl 5.7 Amberlite Drug Resin Amberlite IRP-69 12.0Eudragit L30D-55 57.6 (Enteric polymer) Ethylcellulose Ethocel 10 CPS13.2 Acetyltributyl citrate 3.0 Glycerol Monostearate 2.3 TriethylCitrate 5.8 Magnesium Stearate 0.4 TOTAL 114.5 g/100 mL

EXAMPLE 6 Production of the Suspension Base Containing Immediate ReleaseIbuprofen Dose

TABLE 2 Components of Suspension Base Batch Weight (g) Weight (g)/ for 2Liter Ingredients Tradename 100 mL Batch Purified Water, USP* 65.01300.0 Pregelatinized Starch Ultrasperse M 1.50 30.0 Xanthan Gum, NFXantural 180 0.180 3.60 Glycerin, USP 10.0 200.0 Sucrose, NF Bottler'sFloc 30.0 600.0 Free Polysorbate 80 K NF 0.050 1.00 Citric Acid,Anhydrous, 0.180 3.60 USP Acesulfame K 0.100 2.00 Ibuprofen USP 2.0040.0 Purified Water, USP, 5.49 109.8 q.s. to 100 mL TOTAL 114.5 g/100 mL2290.0 *Sterile Water for Irrigation USP

As indicated in Table 2 above, 1300.0 g of purified water USP werecharged into a mixing tank equipped with a Scott Turbon high shear mixerand mixed at about 500 rpm to about 1000 rpm in order to create a goodvortex. The pregelatinized starch and xanthan gun were then added to themixing tank and mixed for 20 minutes. The glycerin was then addedthereto and mixed for 5 minutes. The sucrose was then added thereto andmixed for 12 minutes. The polysorbate-80 NF, citric acid anhydrous USPand acesulfame K were added sequentially, and then the resulting mixturewas mixed for 10 minutes. The ibuprofen USP was added to the batch andmixed for 20 minutes at about 500 rpm and 1000 rpm. The remainder of thepurified water was then added thereto and mixed for 10 minutes.

EXAMPLE 7 Production of the Suspension Containing Immediate ReleaseIbuprofen Dose And a Phenylephrine-Resin Complex Coated with a SingleSemipermeable Layer

600 mg of the coated phenylephrine particles prepared in accordance withExample 4 were added to a suitable 100 mL volumetric flask and dilutedto a 100.0 mL volume with the suspension base prepared according toExample 6, then mixed end-over-end manually until the resultingsuspension was visually homogenous. The resulting suspension contained100 mg/5 mL of the immediate release ibuprofen dose and 5 mg/5 mL of thephenylephrine dose

EXAMPLE 8 Production of the Suspension Containing Immediate ReleaseIbuprofen Dose And a Phenylephrine-Resin Complex Coated with aSemipermeable Layer and an Outer Protective Enteric Layer

1724.0 mg of the coated phenylephrine prepared in accordance withExample 5, which contained 5.7% of active phenylephrine HCl, was addedto a suitable 100 mL volumetric flask. The resulting suspension was thendiluted to 100.0 mL volume with suspension base as prepared according toExample 6 and mixed end-over-end manually until the resulting suspensionwas homogeneous. The resulting final suspension contained 100 mg/5 mL ofthe immediate release ibuprofen dose and 5 mg/5 mL of the modifiedrelease phenylephrine dose.

EXAMPLE 9 Dissolution Analysis of the Suspension of Example 7 andExample 8

Dissolution Media:

pH 1 (0.1N HCl) Media: 1000 mL of 0.1N HCl was placed in each of threecontainers of a USP Type II apparatus with paddles. A 5.0 mL sample ofthe final suspension produced in Example 7 was then independently addedto each of the three containers and mixed at a speed of 50 r.p.m. at 37°C. until the mixture was visually homogeneous.

This procedure was repeated, but with the substitution of the samplefrom Example 7 with a sample from Example 8.

This procedure was also repeated two additional times, but with thesubstitution of about 20.5 mg of particles from Example 4 and about133.0 mg of particles from Example 5, respectively. These werecalculated based on a dose of about 4.1 mg phenylephrine as a free base.

1 Hour pH Change Media: 750 mL of 0.1 N HCl was placed in each of threeadditional containers of a USP Type II apparatus with paddles. A 5.0 mLsample of the final suspension produced in Example 7 was thenindependently added to each of the three containers and mixed at a speedof 50 r.p.m at 37° C. until the mixture was homogeneous. After 1 hour, a10 ml sample was removed from the vessel, then 250 mL of 0.2M Na₃PO₄ wasadded thereto, which changed the media composition to about 990 mL of0.05M sodium phosphate buffer at a pH of about 6.8.

This procedure was repeated, but with the substitution of the samplefrom Example 7 with a sample from Example 8.

This procedure was then also repeated two additional times, but with thesubstitution of about 20.5 mg of particles from Example 4 and about133.0 mg of particles from Example 5, respectively. These werecalculated based on a dose of about 4.1 mg phenylephrine as a free base.

pH 7.2 (Phosphate Buffer) Media: 1000 mL of 0.05M KH₂PO₄ buffer,adjusted to pH 7.2 with NaOH, was placed in each of three additionalcontainers of a USP Type II apparatus with paddles. A 5.0 mL sample ofthe final suspension produced in Example 7 was then independently addedto each of the three containers and mixed at a speed of 50 r.p.m. at 37°C. until the mixture was visually homogeneous.

This procedure was repeated, but with the substitution of the samplefrom Example 7 with a sample from Example 8.

This procedure was also repeated two additional times, but with thesubstitution of about 20.5 mg of particles from Example 4 and about133.0 mg of particles from Example 5, respectively. These values werecalculated based on a dose of about 4.1 mg phenylephrine as a free base.

Sampling and Analysis:

After 1, 2, 3, 4, 6, 7, and 8 hours, respectively, thereafter, 10 mLsamples of the suspension/buffer mixture were independently removed fromeach of the containers.

Each 10 mL sample was then independently analyzed for ibuprofen andphenylephrine content using a high pressure liquid chromatograph (HPLC)equipped with a Waters® Alliance 2695 Separations Module and a Waters®2996 PDA detector set at a wavelength of 270 nm in order to derivedissolution curves for phenylephrine and ibuprofen at 1, 2, 3, 4, 6, 7,and 8 hours, respectively. Each of the dissolution samples was comparedto a mixed standard containing phenylephrine (free base) at 0.004 mg/mLand ibuprofen (free acid) at 0.10 mg/mL, which correlated to thetheoretical concentration required for 100% release of phenylephrinefree base and ibuprofen free acid.

The mobile phase used in the HPLC was prepared using 20 mM SodiumDodecyl Sulfate (SDS) in 0.2% H₃PO₄/Methanol/Acetonitrile (40/35/25).The injection volume was 50 μL with a run time of approximately 10minutes and a pump flow of 1.0 mL/min. The column used for analysis wasa Phenomenex Luna C8(2), 3 μm, 4.6×75 mm.

The results of the HPLC analysis are illustrated in FIGS. 1 to 4, witheach graphed point representing an average of the percent phenylephrinedissolved in the three vessels.

A comparison of FIGS. 1 and 3 showed that the phenylephrine release ratefrom the ethylcellulose coated particles increased substantially whenthe particles were placed into an ibuprofen-containing suspension. Bycontrast, a comparison of FIGS. 2 and 4 showed that the phenylephrinerelease rate from the particles coated with an inner layer ofethylcellulose and an outer layer of enteric polymer remainedsubstantially the same when the particles were placed into anibuprofen-containing suspension.

1. A liquid pharmaceutical dosage form comprising: a) a first portioncontaining a first active ingredient comprised of an NSAID and/orpharmaceutically acceptable salts thereof, wherein the first activeingredient is released from the dosage form in a substantially immediatemanner upon contact of the dosage form with a dissolution medium; and b)a second portion containing i. ion exchange resin particles having asecond active ingredient bound thereon to form drug-resin complexparticles; ii. a semi-permeable coating layer substantially coveringsaid drug-resin complex particles to form coated particles; and iii. aprotective coating layer substantially covering said coated particles,wherein the second active ingredient is released from the second portionin a modified release manner upon contact of the dosage form with thedissolution medium, and wherein the duration of the therapeutic effectof the second active ingredient as released from the second portion ofthe dosage form is substantially the same as the duration of thetherapeutic effect of the first active ingredient.
 2. The dosage form ofclaim 1 further comprising a vehicle for the administration of the firstportion and the second portion.
 3. The dosage form of claim 2, whereinthe vehicle is selected from the group consisting of solvents,structuring agents, swelling agents, suspending systems, surfactants,sweeteners, buffering agents, preservatives, bacteriostatic agents,colorants, flavoring agents, and mixtures thereof.
 4. The dosage form ofclaim 2, wherein the vehicle is comprised of water, and the dosage formis in the form of a liquid suspension.
 5. The dosage form of claim 2,wherein the vehicle is selected from the group consisting of water, ormixtures of water and a pharmaceutically acceptable water-miscibleco-solvent selected from the group consisting of glycols, alcohols,glycerol, and mixtures thereof.
 6. The dosage form of claim 1, whereinsaid ion exchange resin particles in said second portion are comprisedof styrene/divinyl benzene copolymers, cholestryamines, polacrilinpotassium, and mixtures thereof.
 7. The dosage form of claim 1, whereinsaid semi-permeable coating layer is comprised of one or more agentsselected from the group consisting of cellulose acetate, ethylcellulose,non-enteric polymethacrylates, and mixtures thereof.
 8. The dosage formof claim 1, wherein said protective coating layer is comprised ofenteric polymers selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, cellulose acetate phthalate, polyvinylacetate phthalate,shellac, enteric polymethacrylate-based polymers, and copolymers andmixtures thereof.
 9. The dosage form of claim 1, wherein said protectivecoating layer is comprised of a lipid, a wax, or mixtures thereof. 10.The dosage form of claim 1, wherein said protective coating layer isselected from the group consisting of sucrose fatty acid esters;monoglycerides; diglycerides; triglycerides; glyceryl behenate; glycerylpalmitostearate; glyceryl tristearate; glyceryl trilaurylate; glycerylmyristate; GLYCOWAX-932; lauroyl macrogol-32 glycerides; stearoylmacrogol-32 glyceride; fatty acid esters having a fatty acid chainlength of about C₁₀ to about C₄₀; and mixtures thereof.
 11. The dosageform of claim 1, wherein said protective coating layer is comprised of awax selected from the group consisting of carnauba wax, spermaceti wax,beeswax, candelilla wax, shellac wax, carnuba wax, beeswax,microcrystalline wax, and paraffin wax, and mixtures thereof.
 12. Thedosage form of claim 1, wherein the semi-permeable coating layer furthercomprises, based upon the total dry weight of the semi-permeable coatinglayer, from about 0.1% to about 40% of a plasticizer.
 13. The dosageform of claim 1, wherein the protective coating further comprises, basedupon the total dry weight of the protective coating, from about 0.1% toabout 40% of a plasticizer.
 14. The dosage form of claim 1, wherein theweight ratio of the semipermeable coating layer to the protectivecoating layer is about 10:90 to about 90:10.
 15. The dosage form ofclaim 1, wherein the second portion is comprised of, based upon thetotal dry weight of the second portion, a) from about 5 percent to about80 percent of the first coating layer; b) from about 10 percent to about90 percent of the second coating layer; and c) from about 1 percent toabout 50 percent of the drug-resin complex particles.
 16. The dosageform of claim 1 further comprising, based upon the total weight of thedosage form, from about 0.1% to about 5% of the first portion; and fromabout 0.05% to about 5% of the second portion.
 17. The dosage form ofclaim 1 further comprising, based upon the total weight of the dosageform, a) from about 0.1% to about 5% of the first active ingredient; andb) from about 0.005% to about 1% of the second active ingredient. 18.The dosage form of claim 1 wherein the first active ingredient is apropionic acid derivative or a pharmaceutically acceptable salt thereofand the second active ingredient is phenylephrine or a pharmaceuticallyacceptable salt thereof.
 19. A method for treating pain in a mammal inneed thereof, which comprises administering the dosage form of claim 1in an amount effective for providing pain relief to the mammal for atime period of at least about four hours to about six hours afteradministration of the dosage form.
 20. A method for treating sinuscongestion in a mammal in need thereof, which comprises administeringthe dosage form of claim 1 in an amount effective for providing painrelief to the mammal for a time period of at least about four hours toabout six hours after administration of the dosage form.
 21. A method ofadministering an NSAID and a decongestant in a pharmaceutical dosageform to a mammal in need thereof, said method comprises providing to amammal said dosage form such that the mammal receives an immediaterelease dose of said NSAID or a pharmaceutically acceptable salt thereofupon administration, and a modified release dose of said decongestantover a time period of about 4 hours to about 6 hours afteradministration of said dosage form, wherein no further NSAID ordecongestant is provided during said time period.
 22. A liquidsuspension dosage form comprising: a) a first portion containing anNSAID or a pharmaceutically acceptable salt thereof being released fromthe dosage form in a substantially immediate manner upon contact of thedosage form with a dissolution medium; b) a second portion of particlescontaining a decongestant, said decongestant being released from theparticles in a modified manner upon contact of the dosage form with thedissolution medium; and c) water, or mixtures of water and apharmaceutically acceptable water-miscible co-solvent selected from thegroup consisting of glycols, alcohols, glycerol, and mixtures thereof,wherein the decongestant is released from the second portion in amodified release manner upon contact of the dosage form with thedissolution medium, and wherein the duration of the therapeutic effectof the decongestant as released from the second portion of the dosageform is substantially the same as the duration of the therapeutic effectof the NSAID.
 23. A liquid pharmaceutical dosage form comprising: a) afirst portion containing a first active ingredient comprised of an NSAIDand/or a pharmaceutically acceptable salt thereof, wherein the firstactive ingredient is released from the dosage form in a substantiallyimmediate manner upon contact of the dosage form with a dissolutionmedium; and b) a second portion containing i. ion exchange resinparticles having a second active ingredient bound thereon to formdrug-resin complex particles; ii. a semi-permeable coating layersubstantially covering said drug-resin complex particles to form coatedparticles; and iii. a protective coating layer substantially coveringsaid coated particles, wherein the second active ingredient is releasedfrom the second portion in a modified release manner upon contact of thedosage form with the dissolution medium, and wherein the second activeingredient is the same as or different from the first active ingredient.24. A liquid pharmaceutical dosage form comprising: a) a first portioncontaining a first active ingredient comprised of an NSAID or apharmaceutically acceptable salts thereof, wherein the first activeingredient is released from the dosage form in a substantially immediatemanner upon contact of the dosage form with a dissolution medium; and b)a second portion containing i. cation exchange resin particles having asecond active ingredient bound thereon to form drug-resin complexparticles, said second active ingredient comprised of phenylephrine or apharmaceutically acceptable salt thereof and said cation exchange resinparticles comprised of a sulfonated co-polymer of styrene and divinylbenzene or a co-polymer of methacrylic acid and divinyl benzene; ii. asemi-permeable coating layer substantially covering said drug-resincomplex particles to form coated particles, said semi-permeable coatinglayer comprised of ethylcellulose or non-enteric polymethacrylate; andiii. a protective coating layer substantially covering said coatedparticles, wherein the second active ingredient is released from thesecond portion in a modified release manner upon contact of the dosageform with the dissolution medium, and wherein the duration of thetherapeutic effect of the second active ingredient as released from thesecond portion of the dosage form is about 4 hours to about 6 hours andthe duration of the therapeutic effect of the first active ingredient isabout 4 hours to about 6 hours.